Clinical trials MOSAIC (Andre, Boni et al, 2009)1 (Multicenter International Study of Oxaliplatin, Fluorouracil, and Leueovorin trial) and C-07 (Kuebler, Wieand et al. 2007)2 showed that oxaliplatin added to fluorouracil (FU) and leucovorin (LV) significantly improved disease free survival (DFS) and established oxaliplatin as part of the standard of care for the adjuvant treatment of early-stage colon cancer. In the C-07 trial, 2,409 patients diagnosed with stage II and III colon adenocarcinoma who had undergone potentially curative surgical resection with no evidence of residual malignant disease were randomly assigned to receive either FULV (FU 500 mg/m2 by intravenous [IV] bolus weekly for 6 weeks; leucovorin 500 mg/m2 IV weekly for 0 weeks of each 8-week cycle for three cycles) or FLOX (FULV plus oxaliplatin 85 mg/m2 IV on days 1, 15, and 29 of each cycle). Based on the 2011 analysis with median follow-up of 8 years, FLOX demonstrated superior DFS (HR; 0.82; P=002)(Kuebler, Wieand et at 2007)2. Current NCCN guidelines recommend that all stage III patients, and high risk stage II patients be treated with oxaliplatin. High risk stage II includes patients with perforation, or obstruction or rumors with lymphovascular or perineural invasion, T4 lesions, less than 12 Lymph nodes examined, or grade 3-4 lesions. However, recent analysis of MOSAIC analysis found no statistically significant benefit for either all stage II or high risk stage II patients (Tournigand, Andre et al. 2012)3. The use of oxatiplatin in all early stage colon cancer patients remains controversial not only because it is uncertain which patients actually receive benefit but also because of the toxic side effects associated with oxaliplatin (Cersosimo 2005)4. Thus, stratifying patients with regard to their oxaliplatin benefit is of significant clinical interest.
Recently, several studies (De Sousa, Wang et al. 2013; Marisa, de Reynies et al. 2013; Sadanandam, Lyssiotis et al. 2013) have used unsupervised clustering methods to develop genomic signatures to classify colorectal cancer to different intrinsic subtypes and showed that each subtype has distinct molecular features, clinical significance and prognosis. These groups identified either 3 or 5 intrinsic subtypes with the CCS3, Stem-Like as the poorest prognostic group. The different number of clusters in these publications is not surprising given that different methods and different training, datasets were used. Sadanandam et al's (Sadonandam, Lyssiotis et at 2013)9 five subtypes were correlated, to gene expression patterns of the different cell types located within the normal colonic crypts. De Sousa et al also demonstrated that most of the published gene expression based prognostic assays identify essentially the same group of tumors (mostly stem-like or CCS3 subtypes) as those associated with high risk of relapse. Given that it is now well established that breast cancer subtypes differ regarding their prognosis and their response to treatment, it was reasonable to hypothesize that the clinical behavior of the different colon subtypes may also differ with respect to prognosis and importantly with response to treatment. However, it was not possible to test treatment response in these published studies because the patient cohorts were treated with a variety of agents and were not part of a randomized clinical trial designed to test a particular agent. In contrast the gene expression data which was profiled on archived tumor blocks from NSABP clinical trial C-07 represented an ideal experimental cohort to test whether colon cancer subtypes could be used to predict oxidiplatin benefit. Before the publication of these colon cancer subtypes we had completed the gene expression profiling of 1846 patients from C-07 using our custom nCounter code set using nCounter assays from Nanostring Technologies.